Abstract
High Mobility Group AT-hook 2 (HMGA2) is a chromatin modifier and its overexpression has been found in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Level of Hmga2 expression is fine-tuned by Lin28b-Let-7 axis and Polycomb Repressive Complex 2, in which deletion of Ezh2 leads to activation of Hmga2 expression in hematopoietic stem cells. To elucidate the mechanisms by which the overexpression of HMGA2 helps transformation of stem cells harboring a driver mutation of TET2, we generated an Hmga2-expressing Tet2-deficient mouse model showing the progressive phenotypes of MDS and AML. The overexpression of Hmga2 remodeled the transcriptional program of Tet2-deficient stem and progenitor cells, leading to the impaired differentiation of myeloid cells. Furthermore, Hmga2 was bound to a proximal region of Igf2bp2 oncogene, and activated its transcription, leading to enhancing self-renewal of Tet2-deficient stem cells that was suppressed by inhibition of the DNA binding of Hmga2. These combinatory effects on the transcriptional program and cellular function were not redundant to those in Tet2-deficient cells. The present results elucidate that Hmga2 targets key oncogenic pathways during the transformation and highlight the Hmga2-Igf2bp2 axis as a potential target for therapeutic intervention.
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Acknowledgements
The authors thank the members of the Sashida Laboratory for their discussions during the preparation of this manuscript and Mr. Shinji Kudoh and Dr. Takaaki Ito for their technical help. This work was supported in part by a grant from the Daiichi Sankyo Foundation of Life Science (to GS), the Uehara Memorial Foundation (to GS), the Princess Takamatsu Cancer Research Fund (to GS), the Japanese Society of Hematology (to GS), International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo (to GS), and Grants-in-Aid for Scientific Research (16KT0113, 18H02842, 19K22640 and 19K08842) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.
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Bai, J., Yokomizo-Nakano, T., Kubota, S. et al. Overexpression of Hmga2 activates Igf2bp2 and remodels transcriptional program of Tet2-deficient stem cells in myeloid transformation. Oncogene 40, 1531–1541 (2021). https://doi.org/10.1038/s41388-020-01629-w
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DOI: https://doi.org/10.1038/s41388-020-01629-w
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